Pressure is mounting in the EU to move away from many of the most popular solvents currently in use. Some are facing bans due to their toxicity, such as NMP, dichloromethane and toluene. Additionally, owing to recent international agreements to fight climate change, chemical companies are required to reduce CO2 emissions for which solvents are a major contributor. This is due to the volumes in which they are used (up to 50% of the total mass of chemicals in the manufacture of active pharmaceutical ingredients), on top of the fact that they are sourced from petroleum and incinerated at the end of their lifetimes. In this way, carbon which has been stored in the earth's crust for millions of years as oil is converted to CO2 and released to the atmosphere.
As biomass consumes CO2 to grow, the use of solvents which have been sourced from biomass leads to no net increase in the levels of atmospheric CO2, establishing a closed carbon cycle. In recent years, many bio-based solvents with diverse chemical, physical and solubility properties have been developed such as bio-ethanol, 2-methyltetrahydrofuran (2-MeTHF), dihydrolevoglucosenone (Cyrene®), para-cymene and some ionic liquids. However, bio-based low polarity, low boiling solvents which can potentially replace traditional hydrocarbon solvents such as toluene and hexane, are under-represented (see Sherwood et al. in Green Chem. 2016, 18, p 3990). While 2-MeTHF is a viable option for some applications, it is an ether, and like most commonly used ethers, forms explosive peroxides due to the presence of an easily extractable proton in the alpha-position to the ethereal oxygen. Hexamethyldisiloxane is another option, however its synthesis from biomass is not easy and upon combustion forms large quantities of ash.
This invention relates to the production of a non-peroxide-forming, low-boiling, low-polarity solvent that can potentially replace traditional hydrocarbon solvents such as toluene and hexane, and that can be produced from biomass (or in other words: is bio-based): 2,2,5,5-tetramethyltetrahydrofuran (TMTHF). TMTHF has a low boiling point of ˜111° C. and low ETN value of 0.111, both comparable to toluene. Although TMTHF is an ether by definition as it contains an R—O—R′ group (where R and R′ are alkyl groups), it does not possess the peroxide-forming potential of other ethers such as THF or 2-MeTHF. This is due to the absence of a proton in the α-position relative to the ethereal oxygen. The α-proton in traditional ethers is readily removed by low energy light, forming radicals. Oxygen from the air can react with the radicals to form explosive peroxides. The rate of peroxide forming potential in ethers increases with increasing radical stability: primary α-carbon<<secondary α-carbon<tertiary α-carbon. As TMTHF does not contain any α-protons due to it containing two quaternary ethereal carbons, the potential to form peroxides is removed. The combination of these very favourable properties make TMTHF a rare low-boiling, low-polarity molecule which does not possess peroxide-forming potential and can be easily produced from biomass.
Methods of producing TMTHF from a precursor molecule comprising contacting the precursor with a catalyst have been reported in literature. Especially catalytic methods with 2,5-dimethylhexane-2,5-diol as a precursor have been described.
Denney et al. in J. Org. Chem. 1984, 49, p 2831 disclose a process for the preparation of TMTHF comprising contacting 2,5-dimethylhexane-2,5-diol with pentaethoxyphosphorane as a catalyst in DCM as a solvent.
Vlad & Ungur in Synthesis 1983, 1983, p 216 disclose a process for the preparation of TMTHF comprising contacting 2,5-dimethylhexane-2,5-diol with chlorotrimethylsilane as a catalyst in benzene as a solvent.
Gillis & Beck in J. Org. Chem. 1963, 28, p 1388 disclose a process for the preparation of TMTHF comprising contacting 2,5-dimethylhexane-2,5-diol with DMSO as both a solvent and catalyst.
Yamaguchi et al. in Catal. Today 2012, 185, p 302 disclose a process for the preparation of TMTHF comprising contacting 2,5-dimethylhexane-2,5-diol with hot liquid water in high pressure carbon dioxide as both catalyst and solvent.
Kotkar et al. in J. Chem. Soc. [Perkin 1] 1988, p 1749 disclose a process for the preparation of TMTHF comprising contacting 2,5-dimethylhexane-2,5-diol with aluminium-doped montmorillonite clay as a catalyst. A solvent was not used. However, the yield of the process was only 65%. As a matter of fact, in all aforementioned processes, TMTHF yields did not exceed 78%. A higher yield was achieved in solvent free processes.
DE700036C discloses a process for the preparation of TMTHF comprising contacting 2,5-dimethylhexane-2,5-diol with potassium pyrosulphate in absence of a solvent. The yield was 94.6%.
Olah et al. in Synthesis 1981, p 474 have used Nafion-H™ as a catalyst in the synthesis of TMTHF from 2,5-dimethylhexane-2,5-diol as a precursor. The advantage of a solid catalyst such as Nafion-H is that it can easily be separated from the reaction mixture. The synthesis had a yield of 94%. This leaves 6% for unreacted diol and side-products such as 2,5-dimethyl-2,4-hexadiene and 2,5-dimethyl-4-hexen-2-ol (see below).

The side-products are difficult to separate from TMTHF. It is an objective of the invention to decrease the amount of side-products. It is another objective of the invention to increase the yield of TMTHF above 95%.
Nafion-H™ is a PTFE polymer which has been treated with sulfuric acid. It is very expensive to produce due to the high number of steps and energy required in its production. Furthermore, solid acid catalysts such as Nafion-H™ can become inactive over time. Some solid acid catalysts can be reactivated by calcination to remove organic material from the pores. This process cannot be done to Nafion-H™ due to its relatively low thermal stability, significantly lowering its reusability. Therefore, especially when large quantities of TMTHF need to be produced, the use of Nafion-H™ as a catalyst is disadvantageous. It is a further objective of the invention to provide a process for the preparation of TMTHF which utilizes a catalyst that is cheaper and/or easier to reactivate than Nafion-H™.